Synthesis of coumarin analogs appended with quinoline and thiazole moiety and their apoptogenic role against murine ascitic carcinoma

• Published in: Biomedicine & pharmacotherapy Vol. 112; p. 108707
• Main Authors: Prashanth, T., Avin, B.R. Vijay, Thirusangu, Prabhu, Ranganatha, V. Lakshmi, Prabhakar, B.T., Sharath Chandra, J.N. Narendra, Khanum, Shaukath Ara
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.04.2019; Elsevier
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Antiproliferation; Apoptosis - drug effects; Carcinoma, Ehrlich Tumor - drug therapy; Carcinoma, Ehrlich Tumor - pathology; Cell Line, Tumor; Computer Simulation; Coumarin; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - therapeutic use; Coumarins - toxicity; In vitro; In vivo; Lethal Dose 50; Mice; Quinoline; Quinolines - chemistry; Structure-Activity Relationship; Thiazole; Thiazoles - chemistry; Antiproliferation; Quinoline; In vivo; Coumarin; Thiazole; In vitro
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.108707

[Display omitted] •Novel coumarin analogs were synthesized with verity of substituents.•Docking studies have been done for the potent compound 13f.•In vitro cytotoxicity of 12a-d &13a-f was evaluated against EAC and DLA cell lines.•13f with two methoxy groups on two different rings on coumarin and thiazole moiety was in a leading position.•In vivo studies are conducted on mice models. The synthesis and antiproliferative effect of a series of quinoline and thiazole containing coumarin analogs 12a-d and 13a-f respectively, on mice leukemic cells was performed. The chemical structures of newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and mass spectral analysis. The result indicates that, 7-methoxy-2-oxo-2H-chromene-3-carboxylic acid [4-(4-methoxy-phenyl)-thiazol-2-yl]-amide (13f) showed potent activity against EAC and DLA cells in MTT (15.3 μM), tryphan blue (15.6 μM) and LDH (14.2 μM) leak assay with 5-fluorouracil as a standard. Further, the anti-neoplastic effect of the compound 13f was verified against Ehrlich ascites tumour by BrdU incorporation, TUNEL, FACS and DNA fragmentation assays. Experimental data showed that compound 13f induces the apoptotic cell death by activating apoptotic factors such as caspase-8 &-3, CAD, Cleaved PARP, γ-H2AX and by degrading genomic DNA of cancer cells and thereby decreasing the ascitic tumour development in mice. Besides, compound 13f was also subjected for docking studies to approve the in vitro and in vivo studies. The data revealed that the compound 13f has very good interaction with caspase 3 protein by binding with amino acid Arg 207 through hydrogen bond.